text: Crystal structure analysis showed that the first generation NNRTIs  (for example TIBO, nevirapine and α-APA) bind HIV-1 RT in a “butterfly-like” conformation. These first generation NNRTIs were vulnerable against the common drug-resistance mutations like Tyr-181C and Tyr-188L/H. This triggered the need for finding new and more effective NNRTIs. ITU (imidoylthiourea), a promising series of NNRTIs emerged from α-APA analogs (figure 4).  The ITU compounds were obtained by extending the linker that binds the aryl side groups of the α-APA. A potent ITU compound, R100943, was obtained by an arrangement of the chemical composition of the side groups based on structure-activity relationships (SAR). A crystal structure of the HIV-1/R100943 complex demonstrated that ITU compounds are more flexible than α-APA compound. The ITU compounds showed distinct mode of binding where they bound with "horseshoe" or "U" mode. The 2,6-dichlorophenyl part of R100943 which corresponds chemically to the wing II 2,6-dibromophenyl part of the α-APA occupied the wing I part in the NNIBP whereas the 4-cyanoanilino part of R100943 occupies the wing II position in the NNIBP.
  R100943 inhibited HIV-1 and was considerably effective against a number of key NNRTI-resistant mutants like G190A mutation, which caused high-level resistance to loviride (α-APA) and nevirapine.  G190A mutation was thought to cause resistance by occupying a part of the binding pocket that would otherwise be filled by the linker part of the butterfly shaped NNRTIs. R100943, in the horseshoe mode of binding, is located at a distance of approximately 6.0 Å from G190. When compared with nevirapine and loviride which bind in the butterfly shape the ITU derivatives revealed improved activity against Tyr-181C and Tyr-188L mutants. A structural study suggested that a potent TIBO compound could partly supplement for the effects of the Tyr-181C mutation by moving itself in the non-nucleoside inhibitor binding pocket (NNIBP) of the mutant RT. In this context, R100943 has  torsional freedom that enables the conformational alternations of the NNRTI. This torsional freedom could be used by the ITU derivate to bind to a mutated NNIBP and thus compensating for the effects of a resistance mutation. Nevertheless, the potency of R100943 against HIV-1 resistant mutants was not adequate for it to be considered as an effective drug candidate. Additionally,  the chemical stability of the imidoylthiourea part of the ITU derivative was not favorable for an oral drug.